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Macronutrients, vitamins and minerals intake and risk of esophageal squamous cell carcinoma: a case-control… Jessri, Mahsa; Rashidkhani, Bahram; Hajizadeh, Bahareh; Jessri, Maryam; Gotay, Carolyn Dec 20, 2011

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RESEARCH Open AccessMacronutrients, vitamins and minerals intake andrisk of esophageal squamous cell carcinoma:a case-control study in IranMahsa Jessri1,2, Bahram Rashidkhani3,4*, Bahareh Hajizadeh5, Maryam Jessri6 and Carolyn Gotay7AbstractBackground: Although Iran is a high-risk region for esophageal squamous cell carcinoma (ESCC), dietary factorsthat may contribute to this high incidence have not been thoroughly studied. The aim of this study was toevaluate the effect of macronutrients, vitamins and minerals on the risk of ESCC.Methods: In this hospital-based case-control study, 47 cases with incident ESCC and 96 controls were interviewedand usual dietary intakes were collected using a validated food frequency questionnaire. Data were modeledthrough unconditional multiple logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI),controlling for age, sex, gastrointestinal reflux, body mass index, smoking history (status, intensity and duration),physical activity, and education.Results: ESCC cases consumed significantly more hot foods and beverages and fried and barbecued meals,compared to the controls (p < 0.05). After adjusting for potential confounders, the risk of ESCC increasedsignificantly in the highest tertiles of saturated fat [OR:2.88,95%CI:1.15-3.08], cholesterol [OR:1.53, 95%CI: 1.41-4.13],discretionary calorie [OR:1.51, 95%CI: 1.06-3.84], sodium [OR:1.49,95%CI:1.12-2.89] and total fat intakes [OR:1.48, 95%CI:1.09-3.04]. In contrast, being in the highest tertile of carbohydrate, dietary fiber and (n-3) fatty acid intakereduced the ESCC risk by 78%, 71% and 68%, respectively. The most cancer-protective effect was observed for thecombination of high folate and vitamin E intakes (OR: 0.02, 95%CI: 0.00-0.87; p < 0.001). Controls consumed 623.5times higher selenium, 5.48 times as much b-carotene and 1.98 times as much a-tocopherol as the amount ESCCcases consumed.Conclusion: This study suggests that high intake of nutrients primarily found in plant-based foods is associatedwith a reduced esophageal cancer risk. Some nutrients such as folate, vitamin E and selenium might play majorroles in the etiology of ESCC and their status may eventually be used as an epidemiological marker for esophagealcancer in Iran, and perhaps other high-risk regions.Keywords: Esophageal squamous cell carcinoma, macronutrients, vitamins, minerals, IranBackgroundEsophageal squamous cell carcinoma (ESCC) is the sixthmost common cancer in the world and the fourth mostcommon in the developing countries [1,2] with aremarkable variation in incidence in different regions ofthe world [1-3]. The latest epidemiologic report indi-cated the highest rate of ESCC to be in Iran, followedby other countries located on the “esophageal cancerbelt” such as China, South Africa and France [2,4]. Bothhistologic types of esophageal malignancy (adenocarci-noma and squamous cell carcinoma) are highly lethalwith five-year survival rates of less than 10% [5]. Theincidence rate of esophageal cancer (EC) is 5-10 per100,000 in North America and Europe, and more than100 per 100,000 in China and Iran [3,6]. Although theincidence of EC is higher in males in most parts of theworld [7], in very high incidence areas, such as Iran andChina, the male to female ratio is close to one [7] and* Correspondence: b_rashidkhani@sbmu.ac.ir3Community Nutrition Department, Faculty of Nutrition Sciences and FoodTechnology, Shahid Beheshti University of Medical Sciences, Tehran, IranFull list of author information is available at the end of the articleJessri et al. Nutrition Journal 2011, 10:137http://www.nutritionj.com/content/10/1/137© 2011 Jessri et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.smoking and alcohol are not important risk factors as inwestern countries [8-18].The alarmingly high incidence of ESCC and its equalsex distribution in Iran highlights the likelihood of avery strong environmental risk factor as the main culprit[19]. Gross nutritional deficiencies and unbalanced dietshave long been suspected to play roles in ESCC risk,particularly in high-risk regions of the world wheretobacco smoking and alcohol consumption are not verycommon [7,20]. Several studies have evaluated the effectof micronutrients, such as beta-carotene, folate, vitaminC and vitamin E on ESCC risk [21-30] and some haveproved an inverse association [31-33]. In addition, diet-ary fat [33-35], butter, eggs [28], cholesterol [36] andstarchy foods [28,37] have been directly related to theesophageal cancer risk, while dietary fiber is suggestedto decrease the risk [33,34,38]. Data regarding the roleof protein intake in ESCC etiology are conflicting[28,36,39].While previous studies have mostly focused on fooditems in relation to ESCC risk, studying macro- andmicronutrients could offer advantages mainly throughproviding better understanding of underlying mechan-isms of disease [40]. According to Willet, when an asso-ciation with overall intake of a nutrient is observed, theassociation with the etiology of a particular cancer typeis strengthened, and hence by conducting analyses atthe level of nutrients, maximal information on the can-cer etiology will be obtained [41]. Previous studies inIran have shown a widespread deficient intake of severalnutrients such as riboflavin, vitamin A and vitamin C[42-44]; however, the impact of a wide range of macro-and micronutrient residual intakes in the etiology ofESCC has not been examined in this high-risk popula-tion. The aim of the present study was therefore, toevaluate the effect of major macronutrients, vitaminsand minerals intakes on the risk of ESCC in a case-con-trol study in Iran, and to compare the nutritional ade-quacy of cases and controls.MethodsPopulation and samplingThis hospital-based case-control study was conducted inKurdistan, a high-risk province of Iran. Cases werepatients aged 40-75 years, who visited major generalhospitals and had incident histologically-confirmedESCC. Cases did not have history of carcinoma of othersites and were interviewed within 6 months after theirESCC was diagnosed. Controls were chosen from indivi-duals admitted to the same hospitals as the cases for awide spectrum of acute non-neoplastic diseases includ-ing traumas (25.9%, mostly fractures and sprains), surgi-cal conditions (20.1%, mostly abdominal such as acuteappendicitis and kidney stones), non-traumaticorthopedic conditions (4.2%, mostly disk disorders andback pain) and miscellaneous diseases (49.8%, includingacute eye, nose, skin and throat disorders). Cases andcontrols were frequency-matched according to the sexand age (5-year groups).MeasurementsGenerally, 50 patients with ESCC and 100 hospital con-trols were interviewed face-to-face by professionally-trained interviewers using structured pre-tested ques-tionnaires which evaluated socio-demographic character-istics (age, sex, education, monthly family income, andplace of residence), smoking history (status, durationand intensity), eating habits (food and beverage tem-perature, cooking method), medical history, medicationuse (specifically aspirin and non-aspirin non-steroidalanti-inflammatory drugs (NSAIDs)), gastroesophagealreflux disease (GERD) symptoms (heartburn and acidregurgitation) and familial cancer history [45]. Questionson opium and alcohol consumption were not answeredby our participants due to their cultural barriers andreligious beliefs, and were hence excluded from the ana-lyses. No proxy interviews were required.Weight was measured with subjects clothed minimally,standing on digital scales (Soehne, Berlin, Germany)without shoes and was recorded to the nearest 100grams. Height was measured using a non-stretch tapemeter fixed to a wall with subjects standing withoutshoes and was recorded to the nearest 0.5 cm. Bodymass index (BMI) was then calculated by dividingweight in kilograms by square of height in meters. Phy-sical activity was measured using a validated question-naire comprising of different metabolic equivalent(MET) categories [46], and it was then expressed asMET-hrs/day to estimate the physical activity level ofparticipants [47,48].Two patients were excluded from the analyses sincetheir reported energy intakes were below or above 3standard deviations from the mean, indicating errors inreporting dietary intakes [49]. We further excluded 5patients due to missing information or due to poorresponse to dietary questions. Finally data analyses wereconducted on 47 ESCC cases and 96 controls for whomthe association of dietary patterns and food groupintakes with ESCC risk had been documented previously[45,50].Dietary intake assessmentA validated semi-quantitative food frequency question-naire (FFQ) was used by trained dietitians in face-to-face interviews to evaluate the usual dietary intakes ofparticipants during the previous year [45,50]. Habitualdietary intakes of the controls 1 year before interviewand the cases one year before diagnosis of ESCC wereJessri et al. Nutrition Journal 2011, 10:137http://www.nutritionj.com/content/10/1/137Page 2 of 15evaluated. The FFQ consisted of 125 Iranian food itemsand has previously shown to be a valid and reproducibletool for assessing food and nutrient intakes in Iranianadults [51,52]. Previous studies have revealed good cor-relations between dietary intakes assessed by this FFQand those obtained from 24-h dietary recalls [52]. Acomparison of crude, energy-adjusted and deattenuatedcorrelation coefficients for overall nutrient intakesbetween 24-h dietary recalls and this FFQ have been0.44 and 0.37 in ≤35 and >35 year-olds, respectively,and for individual nutrients it ranged from 0.24 to 0.71in men and from 0.11 to 0.60 in women. On the otherhand, the mean reliability coefficients, ranged from 0.48in ≤35 year-olds to 0.65 in >35 year-olds. This FFQ pro-duced exact agreement rates ranging from 39.6% to68.3% in men and from 39.6% to 59.1% in women,respectively. The validity coefficients, with the samplecorrelation between the questionnaires and biologicalmarkers as the lower limit and the estimates from thetriad method as the upper limit were 0.21-0.56 for pro-tein and 0.37-0.61 for energy [52].Portion sizes of consumed foods were specifiedaccording to the US Department of Agriculture (USDA)standard portion sizes (e.g. apple, 1 medium; bread, 1slice; dairy, 1 cup) and were then converted to grams.When using the USDA portion sizes was impossible,household measures (e.g. beans, 1 tablespoon; chickenmeat, 1 leg or wing; rice, 1 large or small plate) wereused alternatively [53]. Patients were asked to reporttheir consumption frequency on a daily, weekly ormonthly basis, and data were then converted to themean daily intakes assuming one month equals 30.5days.Average daily intake of each food item was calculatedby multiplying the consumption frequency of each foodby its standard item-specific portion size from theexchange list; these scores were then summed to esti-mate nutrient intakes. The estimates of nutrient intakesin the present paper are derived from the dietarysources alone. Since Iranian food composition table(FCT) is incomplete and provides data only on a fewnutrients [54], analyses of energy and nutrients werecarried out using the USDA FCT [55]. However, forsome dairy products (such as Kashk), vetch, wild plum,mint, sweet canned cherry and sour cherry that are notlisted in the USDA FCT, Iranian FCT was used alterna-tively [54]. For analyzing the energy and nutrient con-tents of mixed food items (e.g. pizza), usual restaurantrecipes were used.Statistical analysisFor ordinal variables, chi-square test or Fisher’s exacttest and for continuous variables, Kruskal-Wallis test ort-student test were used to compare case and controlgroups. Macro- and micronutrient intakes were adjustedfor total energy consumption using the residual methodas suggested by Willet and Stampfer [56]. Energy-adjusted nutrients were then categorized into tertiles,due to the appropriateness of tertiles over quartiles forsmaller sample sizes in case-control studies [57]. Tertile1 served as the reference category for all regression ana-lyses. Unconditional multiple logistic regression wasused to estimate the odds ratio (OR) and 95% confi-dence intervals (CI) for the risk of ESCC tumor in thehighest nutrient intake category compared to the lowest.For comparison purposes, we calculated a base regres-sion model and a fully-adjusted model for each analysis.The base model was adjusted for the matching variables,i.e. age (years) and sex (male/female), which are con-trolled for automatically by design. The fully-adjustedmodel, on the other hand, included the following covari-ates: age (years), sex (male/female), GERD symptoms(yes/no), BMI (≤24.9, >24.9 kg/m2kg/m2), smoking sta-tus (never/former/current), smoking intensity and dura-tion (<20, ≥20 pack-years), physical activity (MET)(light/heavy), and education level (illiterate, literate).Potential confounders were included in the multivari-ate models based on the review of literature, comparisonof cases and controls and whether they modified the riskestimates 10% or more. These factors were selectedsince they are potentially related to both the diseaseoutcome (ESCC risk) and also the risk factor (nutrientintakes). Other potential confounders such as monthlyfamily income, place of residence (rural/urban), familialcancer history, cooking method and food and beveragetemperature did not alter the main effect estimates fordietary factors and therefore were not included in thefinal models.As a basis for trend testing, scores were constructedfrom the categorized variables as successive integers andwere used in further analyses. All statistical tests werecarried out using the Statistical Package for SocialSciences, version 16 (SPSS, Inc., Chicago, IL, USA) anda two-tailed P-value of <0.05 was considered statisticallysignificantEthical considerationsThe present study was approved by all regional ethicscommittees in Iran and also the “Ethics Committee ofthe National Nutrition and Food Technology ResearchInstitute”, Shahid Beheshti University of MedicalSciences, Tehran, Iran. Written informed consents weretaken from each subject prior to the interviews.ResultsTable 1 presents the characteristics of 47 cases and 96controls by gender categories. By design, age and sexdistributions were similar among cases and controls.Jessri et al. Nutrition Journal 2011, 10:137http://www.nutritionj.com/content/10/1/137Page 3 of 15The majority of participants, particularly women, had noor limited education (p < 0.001).Despite the significantgender differences (p < 0.001), smoking status, durationand intensity did not differ among cases and controls (p> 0.05). Female cases experienced symptoms of GERDsignificantly more than their control peers (34.5% vs.5.2%; p < 0.001). Among male participants, 11.1% ofESCC cases were overweight and obese (BMI > 24.9),compared to 47.4% in the control group (p = 0.04). Inaddition, BMI values and physical activity level of maleTable 1 Distribution of cases and controls stratified by sex among selected risk factors in a case-control study ofesophageal squamous cell carcinoma in Iran1Variable Male Female P-value2Cases Control Cases ControlParticipants, n 18 (32.1) 38 (67.9) 29(33.3) 58(66.7)Age3, year 60.0(54.75-67.00) 60.0 (54.25-67.00) 57.0(50.00-70.50) 58.0 (48.75-72.25) 0.17≤58 8(44.4) 17(44.7) 17(58.6) 32(55.2)>58 10(55.6) 21(55.3) 12(41.4) 26(44.8)Education, yearIlliterate 14(77.8) 25(65.8) 28(96.6) 55(94.8) <0.001Literate 4(22.2) 13(34.2) 1(3.4) 3(5.2)Monthly family income, US $<300 15 (83.3) 33 (86.8) 28 (96.6) 53 (91.4) 0.14≥300 3 (16.7) 5(13.2) 1 (3.4) 5 (8.6)Place of residenceRural 11(61.1) 20(52.6) 22(75.9) 28(48.3)* 0.80Urban 7(38.9) 18(47.4) 7(24.1) 30(51.7)*Smoking historyNever smoker 5(27.8) 17(44.7) 23(79.3) 51(87.9) <0.001Ex-smoker, pack year < 10 3(16.7) 3(7.9) 3(10.3) 4(6.9)Ex-smoker, pack year≥10 1(5.5) 11(28.9) 3(10.3) 1(1.7)Current smoker, pack year < 20 3(16.7) 4(10.5) 0(0.0) 1(1.7)Current smoker, pack year ≥20 6(33.3) 3(7.9) 0(0.0) 1(1.7)Having symptoms of GERD4 6(33.3) 6(15.8) 10(34.5) 3(5.2)* 0.31Familial cancer history 1(5.6) 0(0.0) 3(10.3) 0(0.0)* 0.48Physical activityLight 13(72.2) 21(55.3)* 16(75.9) 35(60.4)* 0.001Heavy 5(27.8) 17(44.7)* 7(24.1) 23(39.6)*BMI, kg/m2 19.9(3.1)5 24.8(4.0)* 20.8(3.3) 25.7(4.3)* 0.01≤24.9 16(88.9) 20(52.6)* 24(82.8) 27(46.6)>24.9 2(11.1) 18(47.4)* 5(17.2) 31(53.4)NSAIDs useAspirin 2(11.2) 0(0.0) 1(5.6) 0(0.0) 0.63Non-aspirin 3(7.9) 0(0.0) 1(3.4) 0(0.0)Food and beverage temperatureHot 15(83.3) 6(15.8)* 17(58.6) 9(15.5)* 0.03Warm/cold 3(16.7) 32(84.2)* 12(41.4) 49(84.5)*Cooking methodFried/barbecued 8(44.4) 3(7.9)* 6(20.7) 3(5.2)* 0.14Boiled 7(38.9) 21(55.3)* 10(34.5) 49(84.5)*Both 3(16.7) 14(36.8)* 13(44.8) 6(10.3)*GERD: Gastro-esophageal reflux disease; BMI: Body mass index; NSAIDs: Non-steroidal anti-inflammatory drugs*Statistically significant between case and control groups (p < 0.05)1Values are n (%), unless otherwise noted2P-values were estimated using chi-square statistics, Fishers’ exact test or independent t-test for the difference between genders3Median (interquartile range (IQR))4Patients who present with the typical GERD symptoms of heartburn and acid regurgitation5Mean (SD)Jessri et al. Nutrition Journal 2011, 10:137http://www.nutritionj.com/content/10/1/137Page 4 of 15and females differed significantly, with females being lessphysically active and more overweight/obese (p = 0.01).Compared to the controls, cases were more likely toconsume hot foods and beverages (83.3% vs. 15.8%, inmales and 58.6% vs. 15.5%, in females; p < 0.001) andfried/barbecued meals (44.4% vs. 7.9%, in males; and20.7% vs. 5.2%, in females; p = 0.01).The calorie-adjusted mean values for selected macro-nutrients and relative risk estimates of ESCC by tertilesof macronutrient intake residuals are presented inTable 2 and Additional file 1. Cases consumed signifi-cantly more SFA and discretionary calories (energyderived from solid fat and added sugar), compared tothe controls (p = 0.006). On the other hand, controlsconsumed significantly more (n-3) fatty acids, dietaryfiber, carbohydrate and vegetable oil than their casepeers (p = 0.04).In the fully-adjusted model, those in the highest tertileof SFA intake had 2.88 times higher ESCC risk (95% CI:1.15-3.08; p-trend = 0.01), followed by those in the high-est intake tertile of cholesterol (OR: 1.53, 95% CI: 1.41-4.13; p-trend < 0.001), discretionary calorie (OR: 1.51,95% CI: 1.06-3.84; p-trend = 0.002) and total fat intake(OR: 1.48, 95% CI: 1.09-3.04; p- trend = 0.005). On theother hand, being in the highest tertiles of carbohydrate,dietary fiber and (n-3) fatty acid reduced the risk ofESCC by 78%, 71% and 68%, respectively. In the preli-minary age- and sex- adjusted analysis (original match-ing criteria), a positive association also emerged with anincreased protein intake, which was not significant inthe fully-adjusted model.The adjusted mean intakes of vitamin A, b-Carotene,vitamin D, vitamin E, a-Tocopherol, thiamin, riboflavin,vitamin B6, folate, vitamin B12, vitamin C, iron, calcium,Table 2 Relationship between energy-adjusted macronutrient intakes and risk of esophageal squamous cell carcinomain a case-control study in IranMacronutrients Tertiles of Intake1 OR (95%CI)Model 12 Model 23Tertile15 Tertile2 Tertile3 P-trend6 Tertile14 Tertile 2 Tertile 3 P-trend5Total energy, Kcal Number 1.00 (46) 0.80 (0.24-2.13)(48)1.11 (0.25-1.98)(49)0.52 1.00 0.62(0.03-2.65)1.23(0.86-2.14)0.29Total fat, g Number 1.00 (46) 1.23 (1.04-2.95)(46)1.94(1.05-3.28)(51)0.02 1.00 1.11(0.80-2.67)1.48(1.09-3.04)0.005SFA, g Number 1.00 (48) 1.70 (1.21-4.93)(47)3.52 (1.10-3.89)(48)0.01 1.00 1.32(1.20-2.93)2.88(1.15-3.08)0.01PUFA, g Number 1.00 (47) 2.83 (0.34-3.60)(48)0.71 (0.13-1.62)(48)0.98 1.00 1.19(0.42-2.57)0.98(0.31-2.64)0.14MUFA, g Number 1.00 (48) 1.39 (0.95 -2.79)(47)1.39 (0.29-2.16)(48)0.23 1.00 0.97(0.15-1.74)1.19(0.42-2.75)0.81(n-3)fatty acids, g Number 1.00 (48) 0.42 (0.21-0.75)(47)0.51 (0.08-0.90)(48)0.01 1.00 0.86(0.16-0.97)0.32(0.07-0.84)<0.001Dietary fiber, g Number 1.00 (48) 0.72 (0.31-2.18)(47)0.46 (0.01-0.88)(48)<0.001 1.00 0.71(0.02-2.03)0.29(0.13-0.76)0.02Carbohydrate, g Number 1.00 (46) 0.70 (0.31-2.93)(46)0.17 (0.06-0.92)(51)0.04 1.00 0.79(0.32-1.56)0.22(0.05-0.84)<0.001Protein, g Number 1.00 (48) 1.25 (0.59-2.74)(48)1.61 (1.49-4.13)(47)<0.02 1.00 1.13(0.54-1.64)1.93(0.60-3.18)0.52Cholesterol, mg Number 1.00 (47) 0.92 (0.09-1.39)(49)3.71(1.49-2.60)(47)<0.001 1.00 0.68(0.22-1.73)1.53(1.41-4.13)<0.001Vegetable Oil, g6 Number 1.00 (47) 0.59 (0.21-3.58)(47)0.95 (0.16-2.24)(49)0.87 1.00 1.25(0.35-1.93)1.44(0.08-2.23)0.61Discretionary calorie, % total energyintake7 Number1.00 (48) 1.68 (1.07-3.95)(48)2.33(1.58-2.90)(47)<0.001 1.00 1.17(1.02-2.65)1.51(1.06-3.84)0.002OR: Odds ratio; CI: Confidence interval; SFA: Saturated fatty acid; PUFA: Poly unsaturated fatty acid; MUFA: Mono unsaturated fatty acid1Nutrient intakes are adjusted for energy intake using the residual method [56]2Base model; adjusted for age (years) and sex (male/female)3Fully-adjusted model; adjusted for age (years), sex (male/female), gastroesophageal reflux disease symptoms (yes/no), body mass index (≤24.9, >24.9 kg/m2),smoking status (never/former/current), smoking intensity and duration (<20, ≥20 pack-years), physical activity (MET) (light/heavy), and education level (illiterate,literate)4Reference category5The P-value for trend was calculated using the linear regression coefficient for the tertiles of macronutrient intake6Described as fat from vegetable oil, fish, nuts and seeds sources7Described as the energy derived from solid fat and added sugarJessri et al. Nutrition Journal 2011, 10:137http://www.nutritionj.com/content/10/1/137Page 5 of 15phosphorus, methionine and selenium were significantlyhigher among controls compared to ESCC cases (p <0.05), while average adjusted sodium intake was signifi-cantly higher among cases compared to the controls ( p< 0.001) (Additional file 2). Controls consumed 623.5times as much selenium (p < 0.001), 5.48 times as muchb-carotene and 1.98 times as much a-tocopherol as theamount ESCC cases consumed. In the fully-adjustedmodel, the most protective effects against ESCC riskwere associated with higher intakes of folate (OR: 0.08,95% CI: 0.02-0.90; p-trend <0.001) and vitamin E intakes(OR: 0.11, 95% CI: 0.03-0.74; p-trend < 0.001), closelyfollowed by selenium (OR: 0.15, 95% CI: 0.01-0.76; p-trend < 0.001), vitamin B6 (OR: 0.17, 95%CI: 0.05-0.91,p-trend = 0.003) and riboflavin intakes (OR: 0.22, 95%CI: 0.07-0.86; p-trend = 0.01) (Table 3). Being in thehighest tertile of sodium intake residual was associatedwith 1.49 fold increase in the ESCC risk (p < 0.001). Asignificant inverse relationship between ESCC risk andhigher intakes of a-tocopherol, thiamine and potassiumobserved in the base model, disappeared when otherpotential confounders were taken into account.Table 4 shows the OR (95% CI) for the joint effect ofvitamin E and folate intake residuals on ESCC risk.After mutual adjustment for several potential confoun-ders, the combination of high intakes of both chemicalswas associated with a strong protective effect againstESCC risk (OR: 0.02, 95% CI: 0.00-0.87; p < 0.001).There was a statistically significant interaction betweenvitamin E and dietary folate intake when evaluated inthe model (p-value for interaction = 0.03).DiscussionResults of the present study suggest that among macro-nutrients, consuming more carbohydrate, dietary fiberand (n-3) fatty acids and among micronutrients, higherintakes of folate, vitamin E and selenium have the mostprotective effects against ESCC in a high-risk populationin Iran. An increased ESCC risk estimate was observedamong those with highest intakes of SFA, cholesterol,discretionary calorie, sodium and total fat. Most impor-tantly, being in the highest tertile of joint folate andvitamin E intake was associated with 98% reduction inthe ESCC risk.This is the first study in a high-risk population toevaluate the impact of a wide range of macronutrients,minerals and vitamins on risk of ESCC. Similar to pre-vious case-control studies, we found a decreased ESCCrisk associated with higher intakes of nutrients withplant origin and an increased risk for intake of severalnutrients found primarily in animal-based foods[28,29,58-61]. In addition to the differences in nutri-tional composition of animal- and plant-based foodsthat contribute to this effect, heterocyclic amines thatare potent mutagens, and animal carcinogens formedduring cooking of meats are also responsible [62]. Thehighest level of mutagenic activity is produced duringfrying, broiling and barbecuing animal products [59],which could potentially injure the esophageal mucosa[63].Epidemiological studies have shown a positive associa-tion between total fat, cholesterol and SFA intakes withESCC and esophageal adenocarcinoma risk[33,39,57,64-67]. In the present study, more than one-thirds of total energy intake among ESCC cases wasderived from dietary fat and those with higher intakes oftotal fat, SFA, cholesterol and discretionary calories hadan increased risk of ESCC. According to the DietaryGuidelines for Americans 2005 [68], 12-20% of totalenergy intake could be taken from discretionary calories,while in the present study more than 50% of total cal-ories consumed were from discretionary calories, whichis of concern since those in higher tertiles of discretion-ary calorie intake had about 1.5 times higher risk ofESCC. Since all our analyses were adjusted for usualadult BMI, the risk-enhancing effect of high fat diet onESCC observed in the present study was independent ofadiposity, which is a strong risk factor for carcinogen-esis. Further effect modification by BMI revealed thatalthough ESCC risk was higher among those with higherBMI values, p for interaction was not significant (datanot shown). However, this effect is likely to have beenunderestimated since ESCC patients tend to decreasetheir dietary fat intake in an effort to prevent exacerba-tion of reflux symptoms, and hence our result is likelyto have been distorted through underestimation of mag-nitude of true association for dietary fat. Although somestudies have shown an inverse association between ECrisk and intakes of added oil and PUFAs [33], we failedto show a significant relationship.Findings of previous studies have been inconclusiveregarding the role of protein intake in esophageal cancerrisk with some classic studies suggesting an inverse rela-tionship [28,69]. We observed a positive associationbetween protein intake and ESCC risk, which is in linewith more recent studies [33,38,39,57,67,70]; however,this effect was only statistically significant in the age-and sex-adjusted model.High intake of dietary fiber in the present studydecreased ESCC risk by about 70%. Although few stu-dies have questioned the role of dietary fiber in cancerprotection [71-74], most have proved a strong inverseassociation between fiber intake and risk of ESCC, eso-phageal adenocarcinoma and stomach cancer[33,34,38,57,59,60,67,70,75,76]. The role of carbohydrateintake in esophageal cancer risk is not yet clear withsome studies showing a negative association [57], butnot all [77-79]. In the present study, participants withJessri et al. Nutrition Journal 2011, 10:137http://www.nutritionj.com/content/10/1/137Page 6 of 15Table 3 Relationship between energy-adjusted micronutrients intakes and risk of esophageal squamous cell carcinomain a case-control study in Iran1Micronutrients Tertiles of Intake2 OR (95%CI)Model 13 Model 24Tertile16 Tertile2 Tertile3 P-trend7 Tertile15Tertile 2 Tertile 3 P-trend6Vitamin A, RAE Number 1.00 (48) 0.82 (0.19-1.50)(49)0.93 (0.50-2.86)(46)0.94 1.00 0.83(0.09-1.86)0.72(0.38-2.12)0.53b-carotene, μg Number 1.00 (48) 1.59 (0.32-2.86)(47)1.29 (0.51-3.65)(48)0.71 1.00 1.21(0.13-2.68)1.07(0.81-2.13)0.14Vitamin D, μg Number 1.00 (48) 1.10 (0.62-1.75)(47)0.28 (0.17-0.89)(48)<0.001 1.00 0.84(0.39-2.74)0.28(0.02-0.91)<0.001Vitamin E, mg TE Number 1.00 (47) 0.19 (0.03-0.94)(48)0.07 (0.01-0.63)(48)<0.001 1.00 0.32(0.12-0.91)0.11(0.03-0.74)<0.001a-tocopherol, mg Number 1.00 (47) 0.61 (0.12-0.95)(48)0.26 (0.09-0.74)(48)<0.001 1.00 0.86(0.14-1.17)0.47(0.02-1.85)0.31Thiamine, mg Number 1.00 (47) 0.57(0.21-2.73) (48) 0.41 (0.05-0.89)(48)0.04 1.00 0.85(0.61-1.58)0.34(0.06-2.85)0.97Riboflavin, mg Number 1.00 (47) 0.90 (0.22-1.85)(48)0.33 (0.15-0.87)(48)<0.001 1.00 1.90(0.17-2.12)0.22(0.07-0.86)0.01Niacin, mg Number 1.00 (48) 0.37 (0.06-2.10)(47)0.48 (0.10-1.69)(48)0.17 1.00 0.86(0.05-2.63)0.38(0.15-1.82)0.09Panthothenic acid, mgNumber1.00 (47) 0.55 (0.07-2.16)(48)0.86 (0.29-1.11)(48)0.50 1.00 0.86(0.20-1.18)0.49(0.35-2.08)0.74Vitamin B6, mg Number 1.00 (47) 0.48 (0.15-0.79)(47)0.11(0.08-0.93) (49) <0.001 1.00 0.76(0.12-2.33)0.17(0.05-0.91)0.003Folate, μg Number 1.00 (48) 0.26 (0.07-0.90)(47)0.08 (0.01-0.92)(48)<0.001 1.00 0.32(0.01-0.57)0.08(0.02-0.90)<0.001Vitamin B12, μg Number 1.00 (47) 0.58(0.19-1.83) (49) 1.02 (0.39-2.12)(47)0.14 1.00 0.87(0.10-2.61)1.33(0.60-3.03)0.15Vitamin C, mg Number 1.00 (47) 0.69 (0.13-0.75)(49)0.39 (0.11-0.84)(48)0.02 1.00 0.76(0.09-2.43)0.37(0.11-0.93)0.02Iron, mg Number 1.00 (47) 0.51 (0.07-0.93)(49)0.69 (0.17-2.60)(47)0.66 1.00 0.72(0.35-1.63)0.61(0.22-2.48)0.13Calcium, mg Number 1.00 (47) 0.27(0.12-0.87) (49) 0.17 (0.03-0.94)(47)<0.001 1.00 0.51(0.17-1.82)0.49(0.15-0.87)0.03Phosphorous, mg Number 1.00 (48) 1.09 (0.62-3.29)(47)0.77 (0.01-2.56)(48)0.62 1.00 1.35(0.11-2.95)1.31(0.36-2.60)0.92Potassium, mg Number 1.00 (48) 0.51 (0.07-1.98)(47)0.24 (0.11-0.78)(48)0.03 1.00 0.51(0.18-2.93)0.23(0.03-1.76)0.44Sodium, mg Number 1.00 (48) 1.13 (0.22-2.07)(47)1.52 (1.17-3.44)(48)<0.001 1.00 1.17(1.05-2.15)1.49(1.12-2.89)<0.001Zinc, mg Number 1.00 (47) 0.79 (0.16-0.73)(48)0.49 (0.11-0.85)(48)0.01 1.00 1.39(0.58-2.17)0.73(0.12-0.98)0.01Methionine, g Number 1.00 (47) 0.85 (0.09-2.34)(48)0.63 (0.09-0.96)(48)<0.001 1.00 0.79(0.06-1.98)0.29(0.13-0.95)0.004Selenium, μg Number 1.00 (47) 0.32 (0.12-0.94)(48)0.12 (0.04-0.69)(48)0.03 1.00 0.63(0.12-0.91)0.15(0.01-0.76)<0.001OR: Odds ratio; CI: Confidence interval; RAE = Retinol Activity Equivalents; TE= Tocopherol Equivalents1Only micronutrients from food sources are considered.2Nutrient intakes are adjusted for energy intake using the residual method [56]3Base model; adjusted for age (years) and sex (male/female)4Fully-adjusted model; adjusted for age (years), sex (male/female), gastroesophageal reflux disease symptoms (yes/no), body mass index (≤24.9, >24.9 kg/m2),smoking status (never/former/current), smoking intensity and duration (<20, ≥20 pack-years), physical activity (MET) (light/heavy), and education level (illiterate,literate).5Reference category6The P-value for trend was calculated using the linear regression coefficient for the tertiles of micronutrient intakeJessri et al. Nutrition Journal 2011, 10:137http://www.nutritionj.com/content/10/1/137Page 7 of 15higher carbohydrate intakes had markedly reducedESCC risk. However, carbohydrate intake was also nega-tively correlated with fat intakes (correlation coefficient= -0.615) and hence a higher percentage of carbohydratemay just reflect lower intakes of fat and explain itsinverse association with ESCC [57]. In addition, higherconsumption of carbohydrate could be reflection ofmore plant-based food intakes, and especially fruit andvegetable; although in the present research, the correla-tion between carbohydrate and fruits and vegetableintakes was not significant (r = 0.064).It has been suggested that the cancer-protective effectsof fruits and vegetables intake is mediated through theirseveral antioxidants and dietary components, such asfolate, vitamin A, b-carotene, vitamin C and dietaryfiber [64,69,80-83]. Previously we showed an inverseassociation between fruit and vegetable consumptionand risk of ESCC in the same population [50], and inthe present study, after adjustment for fruit and vegeta-ble intake, the association of dietary folate, vitamin Eand selenium with ESCC risk remained significant, sug-gesting an independent protective role for thesenutrients.Epidemiological evidence regarding the role of folateintake in ESCC risk are scanty [21,67,84,85]. Findings ofthe present research are in agreement with those of theprevious studies showing a strong inverse associationbetween dietary folate intake and risk of ESCC[21,22,57,67,85]. However, it is likely that we have moreclearly observed an inverse relationship between folateintake and ESCC compared to other studies [22], sincein Iran there is no mandatory folate fortification and theuse of dietary supplements is very uncommon; hence,folate is mainly taken from diet in this population. Inpopulations with mandatory folate fortification and fre-quent supplement use, most of the population may havesufficient folate intakes to prevent cancer from thesesources and little further benefit may be seen for dietaryfolate intake. On the other hand, the marked cancer-protective effect we observed for high folate intakescould be partly attributed to the comparatively highrates of folate intake deficiency, as more than 90% ofcases and 50% of controls in this study had intakesbelow the Recommended Dietary Allowances (RDA)(data not shown) [86]. Folate is an important cofactor inDNA metabolism and its deficiency has been linked tohigher risk of epithelial tumors [22,23,25,70,87]. Severalmechanisms have been proposed to explain the protec-tive effect of folate, which are mainly focused on preven-tion of hypomethylation and maintenance of the DNArepair system by influencing the nucleotide pool forDNA replication and repair [88-90].Similar to folate, vitamin B2, B6, B12 and methioninehave major roles in one-carbon metabolism. Previousstudies in Iran have reported inadequate riboflavinintakes among patients with esophageal cancer [44].This is in line with findings from this research andthose of previous studies, which have shown protectiveeffects for this nutrient against the risk of EC[28,69,82,91]. Inadequate vitamin B6 intakes amongESCC cases also, might leads to chromosome breakage[92], defective DNA synthesis and methylation andcould increase the ESCC risk [35,67,85].In this study, we failed to observe a significant associa-tion between vitamin B12 intake and ESCC risk. How-ever, it has been suggested that the positive relationshipbetween vitamin B12 and EC risk observed in some stu-dies [67], could be explained by the fact that vitaminB12 is derived exclusively from animal sources andhence may be simply a marker for consumption of ani-mal protein and other factors or nutrients in these foods[67]. It has also been documented that individuals livingin the high ESCC risk regions have significantly lowervitamin B9 and B12 intakes, compared to those living inthe low risk areas [93] and those with vitamin B12 defi-ciency disorders (e.g. pernicious anemia) are at greaterTable 4 Odds ratios (ORs) and 95% confidence intervals (CI) for joint effect of energy-adjusted vitamin E and folateintake on esophageal squamous cell carcinoma risk in a case-control study in Iran1,2FolateModel 13 Model 24Low Medium High Low Medium HighVitamin ELow Number 1.00 (32) 0.51 (0.19-0.72) (15) 0.44 (0.13-0.90) (4) 1.00 0.48 (0.11-0.75) 0.48 (0.11-0.75)Medium Number 0.63 (0.09-0.86) (14) 0.08 (0.01-0.47) (23) 0.07 (0.01-0.69) (11) 0.52 (0.09-0.81) 0.05 (0.01-0.39) 0.05 (0.02-0.41)High Number 0.22 (0.01-0.79) (2) 0.05 (0.00-0.76) (9) 0.01 (0.00-0.79) (33) 0.19 (0.05-0.66) 0.04 (0.01-0.42) 0.02 (0.00-0.87)1Nutrient intakes are adjusted for energy intake using the residual method [62]2P for interaction = 0.033Base model; adjusted for age (years) and sex (male/female)4Fully-adjusted model; adjusted for age (years), sex (male/female), gastroesophageal reflux disease symptoms (yes/no), body mass index (≤24.9, >24.9 kg/m2),smoking status (never/former/current), smoking intensity and duration (<20, ≥20 pack-years), physical activity (MET) (light/heavy), and education level (illiterate,literate)Jessri et al. Nutrition Journal 2011, 10:137http://www.nutritionj.com/content/10/1/137Page 8 of 15risk of EC [94,95]. Overall, causal relationship betweenvitamin B12 intake and ESCC risk is not yet clear andevidence in this regard is lacking. In the present study,high methionine intake was inversely associated withESCC risk, which might be explained through its invol-vement in SAM production, which is necessary forretaining folate in body [96]Higher intakes of vitamin E and vitamin D in thisstudy were associated with about 90% and 70% ESCCrisk reduction, respectively. The finding of a stronginverse association between ESCC with vitamin D intakein this study is consistent with some studies [97,98],although in contrast with others [67]. This contradictioncould be explained by the fact that dietary and supple-mental vitamin D intakes only comprise a relativelysmall proportion of the variation in 25-hydroxy vitaminD levels in the body, and sunlight exposure, skin pig-mentation, geographic region of residence, season, BMI,and differences in vitamin D receptor expressions(genetic differences) are the major predictors of 25(OH)D levels in the body [99,100].Dietary antioxidants (vitamin C, b-carotene and vita-min E) have been shown to decrease the EC risk[27,28,33,38,39,65,82,98,101] through several mechan-isms such as deactivating excited oxygen molecules andpreventing lipid peroxidation. [27,28,38,61,65]. Dietaryantioxidants also play major roles in prevention ofdamage to the mucosa of the upper aerodigestive tractcaused by oxidative stress of smoking and alcohol con-sumption. In the Linxian China trial, supplementationwith a combination of vitamin E, b-carotene, and sele-nium reduced the incidence of esophageal/gastric cardiacancer by 6% [102]; this is consistent with our findingsof a strong inverse association between vitamin E andselenium with the risk of ESCC. Dietary selenium isinversely associated with cell cycle predictors of neoplas-tic progression and the ESCC risk [103-105]. The poten-tial of combined supplementation in the Linxian trial inreducing the EC risk has been mainly attributed to theeffect of selenium, which has a highly deficient intake inChinese population. This is in agreement with results ofour study in which none of the cases had adequate sele-nium intakes, and higher intake of selenium was asso-ciated with 85% reduction in ESCC risk.Vitamin A and b-carotene were not significantly asso-ciated with ESCC risk in our population, which is inline with several studies [57,69,81,98,106] and in con-trast with others [107,108]. Our inability to detect a sig-nificant relationship may be due to considering vitaminA intakes from both plant and animal origins together,while it has been suggested that vitamin A of plant ori-gin is associated with decreased ESCC risk, whereasvitamin A of animal origin increases the level of risk[67,109]. In addition, the protective effect of highcarotene intake observed in some of the previous studiescould have been mediated through high intakes of plant-based foods, which contain different micronutrients andhence contribute to the general effect [59,61,98]. Highintake of vitamin C in this study was associated withmore than 60% reduction in ESCC risk. Vitamin C, asan important antioxidant and inhibitor of endogenoussynthesis of N-nitroso compounds [109-111] preventscarcinogenesis of esophageal cells [110]. However, anintervention trial in China failed to show a reduction inesophageal cancer incidence and mortality in individualstaking 120 mg/day vitamin C for 5.25 years [102].In the present study, higher sodium intake was asso-ciated with almost 50% increase in the ESCC risk. Someepidemiological studies have suggested a role for highersalt intake in carcinogenesis. Although salt is not a car-cinogen per se, it acts as an irritant to the esophagealprotective mucosal layer, which results in inflammatoryregenerative response, increased DNA synthesis and cellproliferation [23] and may also enhance carcinogenesisinduced by other carcinogens [112].Deficiency of several vitamins/minerals has been asso-ciated with higher EC incidence, with the most pro-nounced effect observed in the developing countries [64].Previous studies in Iran have reported high rates of vita-min/mineral deficiencies among EC patients [42-44];which is in line with previous research showing deficiencyof zinc [113], calcium [114] and potassium [97] to bewidespread among EC patients. Calcium intake fromfoods in this study was associated with about 50% reduc-tion in ESCC risk. However, supplemental calcium intakehas previously failed to show beneficial effects on EC risk,which could been explained by the confounding effect ofhigher calcium supplement intakes in the form of GERDmedication by cases compared to the controls [67].This study has several limitations. Firstly, as withother case-control studies, recall bias and selection biaswere inevitable. In case-control studies, there is the pos-sibility that cases may recall their diets differently after acancer diagnosis. However, our participants were gener-ally of low literacy and socioeconomic status with littleknowledge about the role of diet and nutrients in thecancer risk, which should have reduced the possibility ofrecall bias. Moreover, using hospital controls andadministering validated FFQs by trained interviewers ina hospital setting might have further reduced the recallbias and improved comparability of information of casesand controls [115,116]. With regards to the selectionbias, high participation rates (94% among cases and 91%among controls) in this study minimized the potentialfor selective participation according to the lifestyle prac-tices (such as diet).Not having data on participants’ alcohol consumptionwas yet another barrier. Our subjects refrained fromJessri et al. Nutrition Journal 2011, 10:137http://www.nutritionj.com/content/10/1/137Page 9 of 15reporting their alcohol intake due to the fact that con-suming alcohol is legally prohibited in Iran [117,118]. Inaddition, since the import of alcoholic beverages isbanned in Iran, the contents of alcoholic beverages thatIranians consume may differ from those consumed inother countries [117,118]. On the other hand, the Ira-nian FCT does not provide data on any type of alcoholicbeverages [54]. Opium use was also not answered by ourparticipants due to the cultural barriers and sensitivityof this issue among Iranian population [10], whichcould have resulted in confounded estimates in the pre-sent study due to the possible role of opium in ESCCrisk. However, it has been suggested that opium contri-butes to ESCC development only in a subgroup ofpatients and not in the majority [6,19]. In contrast tolow-incidence regions for EC, a much smaller propor-tion of esophageal cancer cases are attributed to alcohol,tobacco and opium use in high-risk regions[9,13,19,119]. This suggests a more prominent role fornutritional deficiencies in EC development in high-riskareas, such as Iran and China, where a larger number ofcases could be attributed to insufficient nutritionalintakes [19,28,42,44,75,102,120].The third limitation is the possibility of some micro-nutrient misclassification due to not having data on sup-plement use. However, it has been suggested that dietarysupplements and fortified foods, mask the beneficialeffect of food intakes in reducing the cancer risk [121]and some of them have independent positive associationwith esophageal cancer risk [85]. In addition, supple-ment intake is very uncommon among our populationsince the majority of participants in the present studywere rural dwellers with little or no education and lowsocioeconomic status. The average monthly familyincome in Iran is about 975 US$ [122] while in the pre-sent study only one of the controls had an incomehigher than this average and there were no significantdifferences between cases and controls (160.91 US $ incases and 189.69 US $ in controls). This might relate tothe sampling method in the present research which wasperformed in general hospitals of one of the high-riskregions of Iran. Generally, lack of information on sup-plement use would most likely have negligible effects onour estimates and if anything, would likely results inunderestimation of association between ESCC and nutri-ent intakes.Another limitation of the present study was using asemi-quantitative FFQ, which despite its common usefor characterizing the habitual dietary intakes, is well-recognized for its weakness in quantification of nutrientintakes [123]. Using a semi-quantitative dietary assess-ment tool limits our conclusions mostly to comparisonsbetween cases and controls and hence conclusionsabout adequacy of diet are relative and should beinterpreted by caution, since these types of comparisonsgenerally overestimate the true effect of exposure on theoutcome. However, the theoretical basics that formedthe food frequency method have been based on thegood correlation of “frequency” of food intake and the“total weights” of the same foods consumed over a sev-eral-day period [124,125]. However, the potential sourceof error in the use of FFQ in the present study resultsfrom lack of a standardized Iranian FCT [118], althoughwe employed the same FCTs used for validation of theIranian FFQ [51,52]. The fundamental concept behindthe calculation of nutrients from FCTs is that the nutri-ent contents of specific foods are relatively constant,and their variability might not be large enough to distortcalculations [126]. In addition, much of the errors relat-ing to sample-to-sample variation in nutrient composi-tion of foods are reduced by using the estimates oflong-term nutrient intakes obtained from the FFQs[126].Another drawback of this study was using nutrientvalues in the statistical analyses without directly refer-ring to the foods which contributed most to the nutrientintake and its variation. According to Willet, an optimalapproach to epidemiologic analysis is to employ bothfoods and nutrients to represent diets [127]; in this waythe case for causality is strengthened when an associa-tion is observed both with the overall intake of a nutri-ent and also with more than one source of that nutrient,especially when the food sources are different. Pre-viously we evaluated the role of food group intakes inthe etiology of esophageal squamous cell carcinoma(ESCC) among the same population [50]; by conductingthe present study, we aimed at providing preliminaryevidence on the extent to which certain nutrients couldinfluence the ESCC risk in such a high-risk region.Another potential source of error is that several natu-rally continuous variables (e.g. BMI, physical activity)were categorized for the purpose of analysis, whichmight have increased the possibility of residual con-founding and decreased the precision and power of thestudy. However, we compensated for this limitation bychoosing categories with multiple sufficiently narrowintervals to decrease the residual confounding and het-erogeneity of subjects within intervals.Additionally, availability of B-vitamins is influenced bydiet, supplement use, alcohol consumption and genericpolymorphism and B-vitamins are all involved in one-carbon metabolism which requires vitamin B2, B6, B9and B12. This complexity added to the problems ofusing estimated intake of nutrients obtained at onepoint in time must be considered when interpreting theresults of this study. Small sample size is also a limita-tion which might have resulted in unstable results andextreme relative risk estimates observed in some of theJessri et al. Nutrition Journal 2011, 10:137http://www.nutritionj.com/content/10/1/137Page 10 of 15subgroups, although this is one of the largest sampleseries in an Iranian population and a number of strongconsistent findings have emerged from this sample[45,50].This study has several strengths. Firstly, eliminatinginformation bias associated with use of proxy dataenabled us to consider numerous potential cofounders.Detailed assessment and adjustment for several impor-tant confounders and total energy intake are otherimportant aspects of this study. We attempted to reducethe measurement error and false-positive effect by calcu-lating nutrient intake residuals standardized for totalenergy intake rather than reporting absolute nutrientvalues. This further accounted for the confounding effectof total energy intake on nutrient intake estimates [127].In the present study, a validated FFQ was used whichprovided subjects with the option of answering in termsof day, week or month which enhanced reporting preci-sion considering the fact that frequency of consumptionis a truly continuous variable [128]. In addition, weasked incident ESCC patients diagnosed within 6 monthof the interview to recall their diets from 1 year beforediagnosis in order to capture a full cycle of seasons sothat responses should not be dependent on the time ofthe year and be representative of habitual long-termintakes [127]. This is of note since short FFQs that havebeen previously used for collecting dietary data are con-sidered the main reasons for the contradictory findingson the role of nutrients in cancer risk [56]. In addition,24-hour dietary recalls which have been used in severalstudies to assess recent or current diets in relation tocancer risk, could severely compromise the accuracy ofmean intake estimates due to the day-to-day variation indietary intakes [129]. Moreover, study design furtherlimits the reliability of short-term recalls in case controlstudies, since dietary recall provides information onpost-diagnosis diet, while the relevant exposures haveoccurred earlier [127]. Given the long latency period ofcancer, remote dietary intakes are far more importantthan the recent diet in cancer incidence studies sincecurrent dietary intake underestimates the true role ofdiet in cancer etiology [130].Finally, evaluating the nutrient-cancer relationship in apopulation without mandatory nutrient fortification,where supplement use is uncommon and nutrientintakes are low has enabled us to capture the associationof nutrients and ESCC more clearly compared to pre-vious studies [22]; as such, results of the present studyshould be considered representative of the influence ofvitamins and minerals that are found naturally in foods.ConclusionIn conclusion, findings of the present study suggest thathigher SFA, cholesterol, discretionary calorie, sodiumand fat intakes significantly increase the risk of ESCC,whereas dietary antioxidants, especially folate, vitamin Eand selenium could prevent the damage to the esopha-gus caused by oxidative stress, even if consumed inmoderate amounts. Our results suggest that dietary pat-terns rich in carbohydrate, dietary fiber and (n-3)PUFAs along with high physical activity and low con-sumption of hot foods and beverages and fried/barbe-cued meals should be promoted in order to preventESCC in Iranian population. However, prospectivecohort studies that evaluate diet before the cancer diag-nosis, as well as interventional studies that addressnutrient deficiencies are warranted to clarify whetherchanges in dietary practices and/or vitamin and mineralsupplementation can reduce the incidence of ESCC inIran.Overall, this study has mainly the character of a pilothypothesis-generating study conducted in a region withlow prevalence of alcohol consumption and high ratesof ESCC, allowing a further search for risk factors ofthis cancer site. It is recommended that these findingsshould be replicated, particularly in comparable samples(i.e., those who have low alcohol and supplement use)to identify dietary factors that could substitute for thedominating role of alcohol and smoking for cancers ofthe upper gastrointestinal tract seen in many Westernsocieties.Additional materialAdditional file 1: Calorie-adjusted mean values among esophagealcancer cases and controls, and range of macronutrient intakes intertile categories of selected macronutrients in a case-control studyin Iran. The file contains information about the mean macronutrientintakes among cases and controlsAdditional file 2: Calorie-adjusted mean values among esophagealcancer cases and controls, and range of micronutrient intakes intertile categories of selected micronutrients in a case-control studyin Iran. The file contains information about the mean micronutrientintakes among cases and controlsAcknowledgementsWe are grateful to all filed investigators, staffs and participants of the presentstudy. This study was supported by grant No. 4030 from the “NationalNutrition and Food Technology Research Institute (WHO CollaboratingCenter)”, Shahid Beheshti University of Medical Sciences, Tehran, Iran.Authors would like to thank Ms. Shaneshin for organizing data files.Author details1Human Nutrition Division, Department of Agricultural, Food and NutritionalSciences, Edmonton Clinic Health Academy, University of Alberta, Edmonton,AB, Canada. 2Alberta Institute of Human Nutrition, Edmonton Clinic HealthAcademy, University of Alberta, Edmonton, AB, Canada. 3CommunityNutrition Department, Faculty of Nutrition Sciences and Food Technology,Shahid Beheshti University of Medical Sciences, Tehran, Iran. 4NationalNutrition and Food Technology Research Institute (WHO CollaboratingCenter), Shahid Beheshti University of Medical Sciences, Tehran, Iran.5Department of Radiation Oncology, Kurdistan University of MedicalJessri et al. Nutrition Journal 2011, 10:137http://www.nutritionj.com/content/10/1/137Page 11 of 15Sciences, Kurdistan, Iran. 6Oral Cancer Research Group, University ofQueensland Center for Clinical Research, Brisbane, QLD, Australia. 7CanadianCancer Society Chair in Cancer Primary Prevention, School of Population andPublic Health, Faculty of Medicine, University of British Columbia, Vancouver,BC, Canada.Authors’ contributionsM.J contributed to the conception and design of this study, data analysis,interpretation and drafting of the manuscript. B.R assisted in conception,design, data acquisition, analysis and drafting of manuscript. B.H collectedthe data and participated in designing the study. M.J. critically reviewed andhelped to draft the manuscript. C.G provided methodological feedback andgave the final approval to the manuscript to be published. 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Nutrition Journal 2011 10:137.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSubmit your manuscript at www.biomedcentral.com/submitJessri et al. Nutrition Journal 2011, 10:137http://www.nutritionj.com/content/10/1/137Page 15 of 15


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